Multi-layer film and medicine container using the same

ABSTRACT

ABSTRACT Disclosed is a multi-layer film comprising: a surface layer having a thickness of 10 to 50 fÊm made of an ethylene-f -olefin copolymer having a density of 0.935 to 0.950 g/cm3, a flexible layer having a thickness of 100 to 200 fÊm made of an ethylene-f -olefin copolymer having a density of 0.860 to 0.930 g/cm3, a barrier layer having a thickness of 10 to 80 fÊm made of a mixed resin containing 60 to 95% by weight of a cyclic olefin polymer and 5 to 40% by weight of an ethylene-f -olefin copolymer having a density of 0.900 to 0.965 g/cm3, and a seal layer having a thickness of 5 to 80 fÊm made of an ethylene-f -olelin copolymer having a density of 0.910 to 0.950 g/cm3. This multi-layer film is suited for use as a material for production of a medicine container  10  because it suppresses adsorption or a medicine by the barrier layer and is also superior in strength and flexibility.

TECHNICAL FIELD

The present invention relates to a multi-layer film which suppressesadsorption of a medicine and a liquid medicine, and a medicine containerusing the same.

BACKGROUND ART

For use in continuous infusion, some medicines are administered in thestate of being mixed with an infusion solution. For use in continuousinfusion, it has been studied to previously form a medicine forinjection into an aqueous dilute solution (namely, pre-mixing).

Bottles and ampuls made of chemically stable glass have hitherto beenused as a medicine container which accommodates an infusion solution.Recently, for the purpose of weight reduction of the medicine containerand improvement in handling property, infusion bags and infusion bottlesmade of a pharmaceutically acceptable plastic have widely been used.Among various known pharmaceutically acceptable plastics, polyethyleneis remarkably superior in handling property because of its high safetyand flexibility in the form of a film, and is also easily disposablebecause no toxic gas is evolved during incineration. Therefore,polyethylene is widely used as a material of the medicine container.

However, since a certain medicine such as nitroglycerin is easilyadsorbed into polyethylene, a problems such as decrease in content ofthe medicine arises in case of administration of mixed injection, whichinterferes with pre-mixing.

Japanese Published Unexamined Patent Application (Kokai Tokkyo Koho Hei)No. 5-293159 proposes a medicine container which uses a cyclic olefinpolymer for the purpose of suppressing adsorption of a medicine.

However, the cyclic olefin polymer has characteristics such as lessadsorption of nitroglycerin but has drawbacks such as hardness andbrittleness, there by causing a problem that properties such as strengthand flexibility of the medicine container are deteriorated.

Furthermore, since the cyclic olefin polymer is inferior in miscibilityand adhesion with the other resin, the medicine container is likely tobe delaminated and lowered in strength. In case the cyclic olefinpolymer and the other resin are bonded using an adhesive resin, aproblem such as dissolution into a medicine arises. Therefore, thesafety is not secured.

Therefore, an object of the present invention is to provide amulti-layer film which is superior in strength, flexibility, heatresistance, and safety suited for use as a medical material, and alsosuppresses adsorption of a medicine and a liquid medicine, and amedicine container using the same.

DISCLOSURE OF THE INVENTION

To achieve the object described above, the multi-layer film of thepresent invention comprises:

a surface layer having a thickness of 10 to 50 μm made of anethylene-α-olefin copolymer having a density of 0.935 to 0.950 g/cm³,

a flexible layer having a thickness of 100 to 200 μm made of anethylene-α-olefin copolymer having a density of 0.860 to 0.930 g/cm³,

a barrier layer having a thickness of 10 to 80 μm made of a mixed resincontaining 60 to 95% by weight of a cyclic olefin polymer and 5 to 40%by weight of an ethylene-α-olefin copolymer having a density of 0.900 to0.965 g/cm³, and

a seal layer having a thickness of 5 to 80 μm made of anethylene-α-olefin copolymer having a density of 0.910 to 0.950 g/cm³.

To achieve the object described above, the medicine container of thepresent invention is characterized in that the multi-layer film of thepresent invention is used so that the surface layer constitutes theouter surface of the medicine container.

In the multi-layer film of the present invention, as shown in themedicine container comprising the film of the present invention, thesurface layer is used so as to constitute the outer surface. That is,the seal layer of the multi-layer film constitutes an innermost layer ofthe medicine container and is directly contacted with a medicineaccommodated in the container.

As the material of the seal layer, an ethylene-α-olefin copolymer, whichis often used in a conventional medical container and exhibits anadsorption ability to nitroglycerin, is used. However, the thickness isset to a small value ranging from 5 to 80 μm and, moreover, the barrierlayer containing a predetermined proportion of the cyclic olefin polymeris provided on the outer surface of the seal layer. On the outer surfaceof the barrier layer, the flexible layer made of the low-densityethylene-α-olefin copolymer and the surface layer made of thehigh-density ethylene-α-olefin copolymer are provided in this order.

According to the multi-layer film with such a layer configuration andthe medicine container using the same of the present invention, it ismade possible to suppress adsorption of the medicine by the barrierlayer and to impart excellent strength and excellent flexibility by theseal layer covering the barrier layer, the flexible layer and thesurface layer while maintaining the miscibility with the barrier layer.

In the multi-layer film of the present invention and the multi-layerfilm used in the medicine container of the present invention, theflexible layer preferably comprises:

-   (a) a material obtained by mixing an ethylene-α-olefin copolymer    having a density of 0.860 to 0.930 g/cm³ with 20% by weight or less    of a high-density polyethylene having a density of 0.940 to 0.970    g/cm³, or-   (b) a laminate of a layer made of an ethylene-α-olefin copolymer    having a density of 0.860 to 0.930 g/cm³ and a layer made of a    material obtained by mixing an ethylene-α-olefin copolymer having a    density of 0.860 to 0.930 g/cm³ with 20% by weight or less of a    high-density polyethylene having a density of 0.990 to 0.970 g/cm³.

By using the material obtained by mixing the ethylene-α-olefin copolymerhaving a predetermined density with the high-density polyethylene, asshown in (a), and the laminate of the layer of the ethylene-α-olefincopolymer having a predetermined density and the layer of thehigh-density polyethylene, as shown in (b), the heat resistance can beimproved without impairing the flexibility of the multi-layer film (andthe medicine container using the same).

In the multi-layer film shown in (a), the ethylene-α-olefin copolymerhaving a density of 0.860 to 0.930 g/cm³ used in the flexible layer maybe a mixture of an ethylene-α-olefin copolymer having a density of 0.860to 0.910 g/cm³ and an ethylene-α-olefin copolymer having a density of0.910 to 0.990 g/cm³. By using the above mixture as the material of theflexible layer, the flexibility of the multi-layer film can be furtherimproved.

In the multi-layer film of the present invention and the multi-layerfilm used in the medicine container of the present invention, theethylene-α-olefin copolymer having a density of 0.860 to 0.930 g/cm³used in the flexible layer is preferably obtained by polymerizing usinga metallocene catalyst. Similarly, the ethylene-α-olefin copolymerhaving a density of 0.900 to 0.965 g/cm³ used in the barrier layer ispreferably obtained by polymerizing using a metallocene catalyst.

As described above, by using those obtained by polymerizing using themetallocene catalyst as the ethylene-α-olefin copolymer used in theflexible layer and the barrier layer, the gas barrier properties andmoisture barrier properties can be improved while satisfactorilymaintaining the flexibility and impact resistance of the multi-layerfilm (medicine container using the same).

Since the multi-layer film of the present invention is used in a medicalpliable plastic container such as medicine container, it preferably hasa total thickness of 130 to 300 μm.

Since the multi-layer film of the present invention is used in a medicalpliable plastic container such as medicine container, the thickness ofthe seal layer is preferably set in order to lower the adsorptionability of the medicine accommodated in the container and to improvevarious characteristics (for example, durability) of the container.Specifically, the thickness of the seal layer is preferably set within arange from 5 to 40 μm in case of attaching great importance to theeffect of preventing adsorption of the medicine, while the thickness ofthe seal layer is preferably set within a range from 40 to 80 μm in caseof attaching more great importance to the durability of the container.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front view showing an embodiment of a medicine container 10according to the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[Multi-Layer Film]

The multi-layer film of the present invention will be described indetail below.

(Barrier Layer)

As described above, the barrier layer in the multi-layer film of thepresent invention is made of a mixed resin containing 60 to 95% byweight of a cyclic olefin polymer and 5 to 40% by weight of anethylene-α-olefin copolymer having a density of 0.900 to 0.965 g/cm³,and the barrier layer has a thickness of 10 to 80 μm.

Examples of the cyclic olefin polymer used in the barrier layer includecopolymer of ethylene and dicyclopentadines, copolymer of ethylene and anorbornene compound, ring-opening polymer of cyclopentadiene derivative,ring-opening copolymer of various cyclopentadiene derivatives, andhydrogenated polymers or copolymers thereof. Among these polymers, ahydrogenated copolymer of ethylene and a norbornene compound or ahydrogenated ring-opening (co)polymer of one or more cyclopentadienederivatives is preferably used to impart high strength and good gas andmoisture barrier properties to the multi-layer film.

Examples of the resin include polymer having a repeating unitrepresented by the following general formula (1) and a repeating unitrepresented by the following general formula (1′) and a polymer having arepeating unit represented by the following general formula (2).

In the formulas (1) and (1′), R¹, R^(1′), R² and R^(2′) are the same ordifferent and represent hydrogen, a hydrocarbon group, or a polar groupsuch as halogen, ester, nitrile or pyridyl, and R¹, R^(1′), R² andR^(2′) may be combined with each other to form a ring; m and m′represent an integer of 1 or more; and n and n′ represent 0 or aninteger of 1 or more.

In the formulas (2), R³ and R⁴ are the same or different and representhydrogen, a hydrocarbon group, or a polar group such as halogen, ester,nitrile or pyridyl, and R³ and R⁴ may be combined with each other toform a ring; x and z represent an integer of 1 or more; and y represents0 or an integer of 1 or more.

The polymer having repeating units represented by the general formulas(1) and (1′) is obtained by polymerizing one or more kinds of monomersusing a known polymerization method or hydrogenating the ring-openingpolymer thus obtained using a conventional method. Specific examples ofthe polymer include hydrogenated polymer manufactured by ZEONCORPORATION [trade name: “ZEONOR®”, specific gravity: 1.01, melt flowrate (MFR): 70 g/10 min. (190° C.), glass transition temperature (Tg):100° C.] and polymer manufactured by Japan Synthetic Rubber Co., Ltd.under the trade name of “ARTON®”.

The polymer having a structural unit represented by the general formula(2) is obtained by the addition copolymerization of one, two or morekinds of norbornene monomers and ethylene using a known method, orhydrogenating the resulting polymer according to a conventional method.Specific examples of the polymer include polymer manufactured by MitsuiChemical Co., Ltd. under the trade name of “APEL® 6509” [specificgravity: 1.02, MFR: 40 g/10 min. (190° C.), glass transition temperature(Tg): 80° C.] and polymer manufactured by Ticona GmbH under the tradename of “Topas®”.

Among the resins including the polymer having structural unitsrepresented by the general formulas (1), (1′) and (2), hydrogenatedresins are superior in heat resistance, transparency and stability, inaddition to gas barrier properties and moisture barrier properties,because they are saturated polymers.

The cyclic olefin polymer used in the present invention preferably has aglass transition temperature (Tg) of 70° C. or higher, and morepreferably from 80 to 150° C. Regarding the range of the molecularweight, the number-average molecular weight <Mn> as measured by gelpermeation chromatography (GPC) using cyclohexane as a solvent ispreferably within a range from 10,000 to 100,000, and more preferablyfrom 20,000 to 500,000. In case an unsaturated bond remained in amolecular chain of the cyclic olefin polymer is saturated withhydrogenation, the hydrogenation ratio is preferably 90% or more, morepreferably 95% or more, and particularly preferably 99% or more.

In the barrier layer, when the proportion of the cyclic olefin polymeris less than 60% by weight, the effect of preventing adsorption of themedicine is lowered. On the other hand, when the proportion of thecyclic olefin polymer exceeds 95% by weight, the flexibility of theentire multi-layer film is deteriorated and also adhesion between thebarrier layer and the other layer is deteriorated.

As described hereinafter, all layers other than the barrier layer in themulti-layer film of the present invention is made of anethylene-α-olefin copolymer, or contains the ethylene-α-olefin copolymeras a main component. Therefore, the entire remaining resin other thanthe cyclic olefin polymer among resins constituting the barrier layer ispreferably an ethylene-α-olefin copolymer.

In the barrier layer, when the proportion of the ethylene-α-olefincopolymer is less than 5% by weight, adhesion between the barrier layerand the other layer is deteriorated. On the other hand, when theproportion of the ethylene-α-olefin copolymer exceeds 40% by weight, theeffect of preventing adsorption of the medicine is lowered because theproportion of the cyclic olefin polymer is reduced.

The ethylene-α-olefin copolymer used to form the barrier layer has adensity within a range from 0.900 to 0.965 g/cm³. When the density ofthe ethylene-α-olefin copolymer used to form the barrier layer is lessthan 0.900 g/cm³, there arises a problem that the heat resistance of themulti-layer film is deteriorated. On the other hand, when the densityexceeds 0.965 g/cm³, there arises a problem that the multi-layer filmbecomes hard and also transparency is deteriorated.

The ethylene-α-olefin copolymer used to form the barrier layer is notspecifically limited as far as it satisfies the above range of thedensity, and conventionally known various ethylene-α-olefin copolymerscan be used. Specific examples thereof include copolymers with a-olefinhaving 3 to 12 carbon atoms, such as propylene, 1-butene, 1-pentene,1-hexene, 4-methyl-1-pentene, 1-heptene, 1-octene, 1-nonene, 1-decene,1-undecene, 1-dodecene or the like. The ethylene-α-olefin copolymer ismore preferably linear in view of the flexibility and strength.

The ethylene-α-olefin copolymer used to form the barrier layer isparticularly preferably produced by using a metallocene catalyst. Whenusing the ethylene-α-olefin copolymer produced by using the metallocenecatalyst, as described above, gas barrier properties and moisturebarrier properties can be improved while satisfactorily maintaining theflexibility and impact resistance of the multi-layer film.

The thickness of the barrier layer is set within the above range takingaccount of the balance between the effect of preventing adsorption ofthe medicine and the flexibility of the entire multi-layer film. Whenthe thickness of the barrier layer is less than 10 μm, the effect ofpreventing adsorption of the medicine is lowered. On the other hand,when the thickness exceeds 80 μm, the flexibility of the entiremulti-layer film is deteriorated. The thickness of the barrier layer isparticularly preferably within a range from 10 to 50 μm.

(Flexible Layer)

As described above, the flexible layer in the multi-layer film of thepresent invention is made of an ethylene-α-olefin copolymer having adensity of 0.860 to 0.930 g/cm³, and the flexible layer has a thicknessof 100 to 200 μm.

In the formation of the flexible layer, an ethylene-α-olefin copolymerhaving a density within the above range is used so as to impart highflexibility to the multi-layer film and the medicine container using thesame. The ethylene-α-olefin copolymer used herein is the same as thosedescribed as for the ethylene-α-olefin copolymer used to form thebarrier layer, except that it has a different density.

The density of the ethylene-α-olefin copolymer used to form the flexiblelayer is particularly preferably from 0.890 to 0.910 g/cm³within theabove range so as to further improve the flexibility of the multi-layerfilm. The copolymer preferably has MFR of 0.5 to 4.0 g/10 min. (190° C.)and also preferably has a melting point of 105 to 120° C.

The ethylene-α-olefin copolymer used to form the flexible layer isparticularly preferably produced by using a metallocene catalyst. Whenusing the ethylene-α-olefin copolymer produced by using the metallocenecatalyst, as described above, gas barrier properties and moisturebarrier properties can be improved while satisfactorily maintaining theflexibility and impact resistance of the multi-layer film.

As the ethylene-α-olefin copolymer having a density of 0.860 to 0.930g/cm³ used to form the flexible layer, a mixture of an ethylene-α-olefincopolymer having a density of 0.860 to 0.910 g/cm³ and anethylene-α-olefin copolymer having a density of 0.910 to 0.940 g/cm³ maybe used. By using the mixture, the flexibility of the multi-layer filmcan be further improved.

The resin used to form the flexible layer (and the flexible layer) maybe an ethylene-α-olefin copolymer having a density of 0.860 to 0.930g/cm³ alone, or a mixture of the above ethylene-α-olefin copolymer and20% by weight or less of a high-density polyethylene having a density of0.940 to 0.970 g/cm³ as shown in (a).

As shown in (b), it also may be a laminate of a layer made of the aboveethylene-α-olefin copolymer and a layer made of a material obtained bymixing an ethylene-α-olefin copolymer having a density of 0.860 to 0.930g/cm³ with 20% by weight or less of a high-density polyethylene having adensity of 0.940 to 0.970 g/cm³.

Also in case of mixing with the high-density polyethylene or forming thelaminate, the density of the entire flexible layer is set within a rangefrom 0.860 to 0.930 g/cm³, similar to the case of using theethylene-α-olefin copolymer alone.

In case the mixed resin (a) or the laminate (b) is used as the resinused to form the flexible layer (and the flexible layer), the heatresistance can be improved without deteriorating the flexibility of themulti-layer film.

The high-density polyethylene, which is mixed with the aboveethylene-α-olefin copolymer or laminated with the copolymer, may be ahomopolymer or a copolymer with α-olefin.

The ratio of the thickness of the respective layers constituting thelaminate (b) is not specifically limited and arbitrary ratio can beselected. The configuration of the laminate is not specifically limitedbut includes, for example, three-layer structure comprising a layer madeof a mixture of an ethylene-α-olefin copolymer and a high-densitypolyethylene as an intermediate layer.

The thickness of the flexible layer is set within the above range so asto impart proper flexibility of the entire multi-layer film. When thethickness of the flexible layer is less than 100 μm, the flexibility ofthe entire flexible layer is deteriorated. On the other hand, when thethickness exceeds 200 μm, the thickness of the entire multi-layer filmis too large.

The thickness of the flexible layer is also set within the above rangeeven if the flexible layer is made of the laminate. The thickness of theflexible layer is particularly preferably within a range from 130 to 180μm.

(Seal Layer)

As described above, the seal layer in the multi-layer film of thepresent invention is made of an ethylene-α-olefin copolymer having adensity of 0.910 to 0.950 g/cm³, and the seal layer has a thickness of 5to 80 μm.

In the formation of the seal layer, an ethylene-α-olefin copolymer isused so that the resulting seal layer endures sterilization under hightemperature conditions (with the blocking resistance) and is easilyheat-sealed and is also pharmaceutically acceptable and does not containa component which is dissolved when contacted with the medicine. Theethylene-α-olefin copolymer used herein is the same as those describedas for the ethylene-α-olefin copolymer used to form the barrier layer,except that it has a different density.

The density of the ethylene-α-olefin copolymer used to form the seallayer is set within the above range in view of the sealabilty.

The thickness of the seal layer is set within the above range takingaccount of the balance between the sealability and the adsorptionability of the medicine. When the thickness of the seal layer is lessthan 5 μm, the sealability is deteriorated. On the other hand, when thethickness exceeds 80 μm, the medicine is likely to be adsorbed into theseal layer and, therefore, the effect of preventing adsorption of themedicine of the entire multi-layer film is lowered.

As described above, when using the multi-layer film of the presentinvention in a medical pliable plastic container such as medicinecontainer, the thickness of the seal layer is preferably set within arange from 5 to 40 μm in case of making a great account of a fact thatadsorption ability of the medicine to be accommodated in the containeris deteriorated, while the thickness of the seal layer is preferably setwithin a range from 90 to 80 μm in case of making a great account of afact that various characteristics (for example, durability) of thecontainer are improved.

(Surface Layer)

As described above, the surface layer in the multi-layer film of thepresent invention is made of an ethylene-α-olefin copolymer having adensity of 0.935 to 0.950 g/cm³ and the surface layer has a thickness of10 to 50 μm.

It is required for the surface layer that it is a layer serving as anouter surface layer when a medicine container is formed of thismulti-layer film and also has a high mechanical strength (especially,tensile strength) and excellent heat resistance, and therefore anethylene-α-olefin copolymer having a density within the above range isused. The ethylene-α-olefin copolymer used herein is the same as thosedescribed as for the ethylene-α-olefin copolymer used to form thebarrier layer, except that it has a different density.

The density of the ethylene-α-olefin copolymer used to form the surfacelayer is preferably from 0.935 to 0.995 g/cm³, and more preferably about0.990 g/cm³, within the above range so as to further improve themechanical strength (especially, tensile strength) and heat resistanceof the surface layer. Furthermore, the copolymer preferably has MFR of1.5 to 2.5 g/10 min. (190° C.) and also preferably has a melting pointof 120 to 130° C.

The thickness of the surface layer is set within the above range takingaccount of the balance between the mechanical strength (especially,tensile strength), heat resistance and thickness of the entiremulti-layer film.

(Method of Producing Multi-Layer Film)

The multi-layer film can be produced by using conventionally knownvarious methods such as water-cooling coextrusion inflation method,coextrusion T-die method and the like.

Since the multi-layer film of the present invention is used in a medicalpliable plastic container such as medicine container, the totalthickness is set within a range from 180 to 300 μm in the production ofthe multi-layer film. When the total thickness is less than 130 μm, thestrength of the medicine container is likely to be lowered. On the otherhand, when the total thickness exceeds 300 μm, the flexibility of themedicine container is deteriorated and the handling property is likelyto be deteriorated.

[Medicine Container]

The medicine container of the present invention will be described belowwith reference to FIG. 1 showing an embodiment of the medicinecontainer.

FIG. 1 is a front view showing an embodiment of a medicine container(liquid medicine bag) using the multi-layer film of the presentinvention.

A medicine container 10 shown in FIG. 1 is produced by cutting twomulti-layer films of the present invention using a conventional method,laying the respective multi-layer films so that each seal layerconstitutes an inner layer, heat-sealing a peripheral portion 22 of themulti-layer film, and attaching a port member 20 to the peripheralportion 22 using a means such as heat sealing.

The method of producing the medicine container of the present inventionis not limited to the above method and the medicine container may alsobe formed, for example, by heat sealing after forming into a tube sothat the seal layer of the multi-layer film faces inside.

As the conditions for heat sealing of the multi-layer film, thetemperature within a range from 130 to 200° C. can be employed. In thecase of a film having a thickness of about 250 μm, sealing can becompleted in a short time such as about 0.5 to 6 seconds at atemperature within the above range.

It is preferred to use, as the port member 20, a resin having excellentfusibility with the seal layer in the multi-layer film, e.g. those madeof polyethylene. In case of the port member 20 made of polyethylenehaving a melting point of about 120 to 130° C., heat sealing may beconducted by pre-heating the port member for several seconds and heatingat about 140 to 170° C. for about 0.5 to 5 seconds.

Preferred examples of the medicine, which can be accommodated in themedicine container, include isosorbide nitrate, nicardipinehydrochloride, midazolam and edaravone, in addition to theabove-mentioned nitroglycerin. These medicines are liable to be adsorbedinto a medicine container made of polyethylene and adsorption can beprevented by accommodating in the medicine container composed of themulti-layer film of the present invention.

The form of the medicine, which can be accommodated in the medicinecontainer of the present invention includes, for example, powder, inaddition to the above-mentioned aqueous solution.

In the form of the medicine container of the present invention, forexample, two or more chamber partitioned with a communicatable partitionwall is formed, in which one chamber can accommodate a powderedmedicine, while the other chamber can accommodate a solution of thepowdered medicine.

Examples

The following Examples and Comparative Examples further illustrate thepresent invention.

[Forming of Multi-Layer Film and Medicine Container]

In the following Examples and Comparative Examples, resins used to forma multi-layer film are as follows.

Resin A: ethylene-1-butene copolymer [manufactured by Mitsui ChemicalCo., Ltd. under the trade name of “ULTZEX® 4020B”, density: 0.940 g/cm³,MFR: 2.1 g/10 min. (190° C.)]

Resin B: ethylene-1-butene copolymer [manufactured by Mitsui ChemicalCo., Ltd. under the trade name of “ULTZEX® 3020B”, density: 0.930 g/cm³,MFR: 2.1 g/10 min. (190° C.)]

Resin C: metallocene catalyst ethylene-1-hexene copolymer [manufacturedby Mitsui Chemical Co., Ltd. under the trade name of “Evolue®”, density:0.905 g/cm³, MFR: 1.5 g/10 min. (190° C.)]

Resin D: high-density polyethylene [manufactured by Mitsui Chemical Co.,Ltd. under the trade name of “HI-ZEX®”, density: 0.965 g/cm³, MFR: 15g/10 min. (190° C.)]

Resin E: ethylene-tetracyclododecene copolymer [manufactured by MitsuiChemical Co., Ltd. under the trade name of “APEL® 6509”, specificgravity: 1.02, MFR: 40 g/10 min. (190° C.), glass transitiontemperature: 80° C.]

Resin F: ethylene-tetracyclododecene copolymer [manufactured by MitsuiChemical Co., Ltd. under the trade name of “APEL® 8008”, specificgravity: 1.02, MFR: 40 g/10 min. (190° C.), glass transitiontemperature: 70° C.]

Resin G: hydrogenated ring-opening polymer of norbornene monomer[manufactured by ZEON CORPORATION under the trade name of “ZEONOR®1020R”, specific gravity: 1.01, MFR: 20 g/10 min. (190° C.), glasstransition temperature: 105° C.]

Resin H: ethylene-1-butene copolymer [manufactured by Mitsui ChemicalCo., Ltd. under the trade name of “ULTZEX® 2010B”, density: 0.920 g/cm³,MFR: 1.0 g/10 min. (190° C.)]

Resin I: ethylene-1-butene copolymer [manufactured by Mitsui ChemicalCo., Ltd. under the trade name of “TAFMER® A0585B”, density: 0.885g/cm³, MFR: 0.5 g/10 min. (190° C.)]

Example 1

The resin A, the resin C, a mixed resin containing the resin E and theresin A in a weight ratio of 3:1 [mixing ratio of a cyclic olefinpolymer (CO): 75% by weight] and the resin A were respectively used asthe surface layer, the flexible layer, the barrier layer and the seallayer.

The surface layer, the flexible layer, the barrier layer and the seallayer were laid one upon another in this order, and then a multi-layerfilm having a total thickness of 230 μm (each of constituent layersformed from the side of the surface layer in the above order has athickness of 20 μm, 170 μm, 30 μm or 10 μm) was formed by awater-cooling coextrusion inflation method.

Using the resulting multi-layer film, a medicine bag (medicinecontainer) 10 shown in FIG. 1 was produced. Polyethylene was used as thematerial of a port member 20. Sealing of the port member 20 wasconducted at 140 to 150° C. for 3 seconds, while sealing of a peripheralportion 22 was conducted at 155° C. for 4.5 seconds.

Example 2

The resin A, a mixed resin containing the resin C and the resin D in aweight ratio of 95:5 [mixing ratio of a high-density polyethylene(HDPE): 5% by weight], a mixed resin containing the resin F and theresin C in a weight ratio of 3:1 [mixing ratio of CO: 75% by weight] andthe resin B were respectively used as the surface layer, the flexiblelayer, the barrier layer and the seal layer.

The surface layer, the flexible layer, the barrier layer and the seallayer were laid one upon another in this order, and then a multi-layerfilm having a total thickness of 230 μm (each of constituent layersformed from the side of the surface layer in the above order has athickness of 20 μm, 175 μm, 20 μm or 15 μm) was formed by awater-cooling coextrusion inflation method.

In the same manner as in Example 1, except that the above multi-layerfilm was used, a medicine bag 10 shown in FIG. 1 was produced.

Example 3

In the same manner as in Example 2, except that the barrier layer wasmade of a mixed resin containing the resin F and the resin C in a weightratio of 3:2 [mixing ratio of CO: 60% by weight], a multi-layer film(total thickness: 230 μm) was formed and a medicine bag was produced.

Example 4

In the same manner as in Example 2, except that the thickness of theflexible layer was changed to 160 μm and the thickness of the seal layerwas changed to 30 μm, a multi-layer film (total thickness: 230 μm) wasformed and a medicine bag was produced.

Example 5

In the same manner as in Example 2, except that the thickness of theflexible layer was changed to 155 μm and the thickness of the barrierlayer was changed to 40 μm, a multi-layer film (total thickness: 230 μm)was formed and a medicine bag was produced.

Example 6

In the same manner as in Example 2, except that the barrier layer wasmade of a mixed resin containing the resin E and the resin C in a weightratio of 3:1 [mixing ratio of CO: 75% by weight], a multi-layer film(total thickness: 230 μm) was formed and a medicine bag was produced.

Example 7

In the same manner as in Example 2, except that the barrier layer wasmade of a mixed resin containing the resin E, the resin F and the resinC in a weight ratio of 3:3:2 [mixing ratio of CO: 75% by weight], amulti-layer film (total thickness: 230 μm) was formed and a medicine bagwas produced.

Comparative Example 1

In the same manner as in Example 1, except that the mixing ratio of theresin E to the resin A of the barrier layer was changed to 1:1 [mixingratio of CO: 50% by weight], a multi-layer film (total thickness: 230μm) was formed and a medicine bag was produced.

Comparative Example 2

In the same manner as in Example 1, except that the thickness of theflexible layer was changed to 100 μl m and the thickness of the seallayer was changed to 90 μm, a multi-layer film (total thickness: 230 μm)was formed and a medicine bag was produced.

Example 8

The resin A, a mixed resin containing the resin H, the resin I and theresin D in a weight ratio of 25:70:5 [mixing ratio of HDPE: 5% byweight], a mixed resin containing the resin G and the resin A in aweight ratio of 3:1 and the resin B were respectively used as thesurface layer, the flexible layer, the barrier layer and the seal layer.

The surface layer, the flexible layer, the barrier layer and the seallayer were laid one upon another in this order, and then a multi-layerfilm having a total thickness of 240 μm (each of constituent layersformed from the side of the surface layer in the above order has athickness of 20 μm, 150 μm, 20 μm or 50 μm) was formed by awater-cooling coextrusion inflation method.

In the same manner as in Example 1, except that the above multi-layerfilm was used, a medicine bag 10 shown in FIG. 1 was produced.

Example 9

In the same manner as in Example 8, except that the thickness of thesurface layer, that of the flexible layer, that of the barrier layer andthat of the seal layer were respectively changed to 20 μm, 130 μm, 10 μmand 80 μm, a multi-layer film (total thickness: 240 μm) was formed and amedicine bag was produced.

Example 10

In the same manner as in Example 8, except that the thickness of thesurface layer, that of the flexible layer, that of the barrier layer andthat of the seal layer were respectively changed to 20 μm, 160 μm, 10 μmand 50 μm, a multi-layer film (total thickness: 240 μm) was formed and amedicine bag was produced.

Comparative Example 3

In the same manner as in Example 8, except that the thickness of thesurface layer, that of the flexible layer, that of the barrier layer andthat of the seal layer were respectively changed to 20 μm, 120 μm, 10 μmand 90 μm, a multi-layer film (total thickness: 240 μm) was formed and amedicine bag was produced.

The layer configurations of the multi-layer films obtained in the aboveExamples and Comparative Examples are summarized in Table 1 and Table 2.

TABLE 1 Comparative Examples Examples 1 2 3 4 5 6 7 1 2 Surface layerKind of resin A A A A A A A A A Thickness (μm) 20 20 20 20 20 20 20 2020 Flexible layer Kind of resin C C + D C + D C + D C + D C + D C + D CC Mixing ratio (weight ratio) — 95:5 95:5 95:5 95:5 95:5 95:5 — —Proportion of HDPE (% by weight) — 5 5 5 5 5 5 — — Thickness (μm) 170175 175 160 155 175 175 170 100 Barrier layer Kind of resin E + A F + CF + C F + C F + C E + C E + F + C E + A E + A Mixing ratio (weightratio) 3:1 3:1 3:2 3:1 3:1 3:1 3:3:2 1:1 3:1 Proportion of CO (% byweight) 75 75 60 75 75 75 75 50 75 Thickness (μm) 30 20 20 20 40 20 2030 20 Seal layer Kind of resin A B B B B B B A A Thickness (μm) 10 15 1530 15 15 15 10 90

TABLE 2 Examples Comparative 8 9 10 Example 3 Surface layer Kind ofresin A A A A Thickness (μm) 20 20 20 20 Flexible layer Kind of resinH + I + D H + I + D H + I + D H + I + D Mixing ratio (weight ratio)25:70:5 25:70:5 25:70:5 25:70:5 Proportion of HDPE (% by weight) 5 5 5 5Thickness (μm) 150 130 160 120 Barrier layer Kind of resin G + A G + AG + A G + A Mixing ratio (weight ratio) 3:1 3:1 3:1 3:1 Proportion of CO(% by weight) 75 75 75 75 Thickness (μm) 20 10 10 10 Seal layer Kind ofresin B B B B Thickness (μm) 50 80 50 90

In Table 1 and Table 2, “C+D” means that two or more kinds of resins(for example, resin C and resin Din this case) are mixed to form a mixedresin, while “C, D” means that two or more kinds of resins (for example,resin C and resin D in this case) are laminated.

[Evaluation Test]

Test Example 1

Each medicine bag (medicine container) obtained in Examples 1 to 7 andComparative Examples 1 to 2 was filled with 100 mL of a 0.005%nitroglycerin solution, subjected to steam sterilization under highpressure at 106° C. for 40 minutes, and then stored at 60° C. for 2weeks. During the storage, the containers were allowed to stand in thestate of being laid on the horizontal surface and the contact areabetween the nitroglycerin solution and the containers was controlled toabout 160 cm². Then, the concentration of nitroglycerin in the solutionafter storage for 2 weeks was measured by high-performance liquidchromatography (HPLC) and a ratio of the resulting concentration to aninitial concentration (0.005%) was determined and taken as a retentionratio (%).

As a control, a glass ampul was filled with 100 mL of a 0.005%nitroglycerin solution and a retention ratio (%) after storage under thesame conditions was determined. Furthermore, a difference (point)between the retention ratio (%) of this control and the retention ratioof the Examples and Comparative Examples was determined.

Test Example 2

In the same manner as in Test Example 1, except that a 0.005% isosorbidenitrate solution was used in place of the nitroglycerin solution, steamsterilization under high pressure and storage at 60° C. for 2 weeks wereconducted. Then, the concentration of isosorbide nitrate in the solutionafter storage for 2 weeks was measured by HPLC and a ratio of theresulting concentration to an initial concentratio was determined andtaken as a retention ratio (%) in the same manner as in Test Example 1.

In the same manner as in Test Example 1, a control test using a glassampul was conducted and a difference (point) between the retention ratio(%) of this control and the retention ratio of the Examples andComparative Examples was determined.

Test Example 3

With respect to the medicine bag (medicine containers) obtained inExamples 8 to 10 and Comparative Example 3, the same test as in TestExample 2 was conducted.

The above results are shown in Table 3.

TABLE 3 Retention ratio (difference with control (point) Test Example 1Test Example 2 (Nitroglycerin solution) (Isosorbide nitrate solution)Example 1 97.0% (+0.1) 98.6% (−0.2) Example 2 96.0% (−0.9) 96.6% (−2.2)Example 3 93.0% (−3.9) 95.5% (−3.3) Example 4 95.8% (−1.1) 96.7% (−2.1)Example 5 96.4% (−0.5) 97.9% (−0.9) Example 6 96.8% (−0.1) 98.8% (0)    Example 7 96.2% (−0.7) 98.1% (−0.7) Example 8 — 98.6% (−0.2) Example 9 —97.0% (−1.8) Example 10 — 98.5% (−0.3) Comparative  85.1% (−11.8) 92.3%(−6.5) Example 1 Comparative  83.2% (−13.7) 92.0% (−6.8) Example 2Comparative — 92.8% (−6.0) Example 3 Control 96.9% 98.8%

As shown in Table 1, the multi-layer films used in Examples 1 to 7 andthe medicine bags of Examples 1 to 7 correspond to the multi-layer filmand the medicine container using the same of the present invention.

As is apparent from the results of the retention ratio shown in Table 3,according to the medicine containers of Examples 1 to 7, the adsorptionamount of the medicine could be held down to the minimum. For example,the adsorption amount (retention ratio) was the same as or slightly morethan the case of using the glass ampul. Furthermore, all of the medicinecontainers of Examples 1 to 7 had a sufficient strength suited for useas the medicine container, and excellent flexibility and excellent heatresistance. Since the medicine container (especially a seal layer) ismade mainly of an ethylene-α-olefin copolymer, it was superior in safetysuited for use as a medical material.

On the other hand, in Comparative Example 1 wherein the barrier layerhas a small content of the cyclic olefin polymer and Comparative Example2 wherein the seal layer which is directly contacted with the liquidmedicine is too thick, the adsorption amount of the medicine was verylarge.

As shown in Table 2, the multi-layer films used in Examples 8 to 10 andthe medicine bags of Examples 8 to 10 correspond to the multi-layer filmand the medicine container using the same of the present invention.

As is apparent from the results of the retention ratio shown in Table 3,according to the medicine containers of Examples 8 to 10, the adsorptionamount of the medicine could be held down to the minimum. Moreover,since the seal layer had a sufficient thickness, the medicine containeritself was remarkably superior in durability.

On the other hand, in the medicine container of Comparative Example 3wherein the seal layer is too thick, the adsorption amount of themedicine was very large.

As is apparent from the above results, the multi-layer film and themedicine container using the same of the present invention can be suitedfor use as a medical material for accommodating and storing a medicineand a liquid medicine, especially in the application where a medicine,which is likely to be adsorbed into polyethylene, such as nitroglycerinis pre-mixed.

INDUSTRIAL APPLICABILITY

The multi-layer film of the present invention comprises a barrier layercontaining a cyclic olefin polymer, and a flexible layer made of alow-density ethylene-α-polyolefin copolymer, a surface layer made of ahigh-density ethylene-α-polyolefin copolymer and a seal layer whichcovers the barrier layer, which are provided on the outer surface of thebarrier layer. The multi-layer film can suppress adsorption of amedicine by the barrier layer and is suited for use as a material forthe production of a medicine container because of its excellent strengthand excellent flexibility.

1. A multi-layer film comprising: a surface layer having a thickness of10 to 50 μm made of an ethylene-α-olefin copolymer having a density of0.935 to 0.950 g/cm³, a flexible layer having a thickness of 100 to 200μm made of an ethylene-α-olefin copolymer having a density of 0.860 to0.930 g/cm³, a barrier layer having a thickness of 10 to 80 μm made of amixed resin containing 60 to 95% by weight of a cyclic olefin polymerand 5 to 40% by weight of an ethylene-α-olefin copolymer having adensity of 0.900 to 0.965 g/cm³, and a seal layer having a thickness of5 to 80 μm made of an ethylene-α-olefin copolymer having a density of0.910 to 0.950 g/cm³.
 2. The multi-layer film according to claim 1,wherein the flexible layer comprises a material obtained by mixing anethylene-α-olefin copolymer having a density of 0.860 to 0.930 g/cm³with 20% by weight or less of a high-density polyethylene having adensity of 0.940 to 0.970 g/cm³.
 3. The multi-layer film according toclaim 1, wherein the flexible layer comprises a laminate of a layer madeof an ethylene-α-olefin copolymer having a density of 0.860 to 0.930g/cm³ and a layer made of a material obtained by mixing anethylene-α-olefin copolymer having a density of 0.860 to 0.930 g/cm³with 20% by weight or less of a high-density polyethylene having adensity of 0.940 to 0.970 g/cm³.
 4. The multi-layer film according toany one of claims 1 to 3, wherein the ethylene-α-olefin copolymer havinga density of 0.860 to 0.930 g/cm³ used in the flexible layer is obtainedby polymerizing using a metallocene catalyst.
 5. The multi-layer filmaccording to claim 2, wherein the ethylene-α-olefin copolymer having adensity of 0.860 to 0.930 g/cm³ used in the flexible layer is a mixtureof an ethylene-α-olefin copolymer having a density of 0.860 to 0.910g/cm³ and an ethylene-α-olefin copolymer having a density of 0.910 to0.940 g/cm³.
 6. The multi-layer film according to any one of claims 1 to5, wherein the ethylene-a-olefin copolymer having a density of 0.900 to0.965 g/cm³ used in the barrier layer is obtained by polymerizing usinga metallocene catalyst.
 7. The multi-layer film according to any one ofclaims 1 to 6, which has a total thickness of 130 to 300 μm.
 8. Themulti-layer film according to any one of claims 1 to 7, wherein the seallayer has a thickness of 5 to 40 μm.
 9. The multi-layer film accordingto any one of claims 1 to 7, wherein the seal layer has a thickness of40 to 80 μm.
 10. A medicine container which uses the multi-layer film ofany one of claims 1 to 9 so that the surface layer constitutes the outersurface of the medicine container.